Vaccination is one of the most successful and cost-effective ways of preventing infectious disease. The development of effective vaccines for infections of the gastrointestinal tract however has been disappointing. The need for these vaccines is crucial since diarrheal diseases due to infectious agents of the gut are the second leading infectious cause of death in infants and young children world wide. Some of the Infectious agents that cause diarrheal diseases include rotavirus, pathogenic Escherichia coli, Shigella spp., Salmonella spp., Cryptosporidium pan/urn, Entamoeba histolytica, and Vibrio cholera. The reason for the lack of suitable vaccines for enteric pathogens is the lack of an effective adjuvant that can be delivered orally with the vaccine to increase its potency at stimulating an immune response. Most experimental oral adjuvants are ineffective or maintain some degree of toxicity. To address this problem, we propose to couple synthetic peptides from enteric pathogens to a safe and stable adjuvant, aluminum oxide nanoparticles for oral immunization. The peptides will be coupled to the nanoparticles in a way that preserves their native conformation in order to optimize the immune response to recognize the native pathogen. Since very few small animal models of enteric disease and immunity exist, we will use the human pathogen Helicobacter pylori (H. pylori) to infect the mouse gastric mucosa and we will test this technology by 1) Identifying epitopes on H. pylori CagL that are crucial for binding of the bacteria to host cells using an antibody blocking assay with human cell lines, 2) Testing the ability of those CagL epitopes, coupled to aluminum oxide nanoparticles, to induce protective immunity when delivered to mice prior to challenge, 3) Testing the ability of those CagL epitopes, coupled to aluminum oxide nanoparticles, to induce antibodies that block pathogenic and carcinogenic events due to H. pylori infection, and 4) Evaluating the antibody response of infected human subjects to determine if these blocking antibodies are induced by natural infection in order to determine if the induction of these antibodies by vaccination would be beneficial to human patients. A reduction of infection, inflammation, or carcinogenesis in the H. pylori model by immunization with stable, targeted peptide epitopes coupled to nanoparticles would provide compelling evidence for subsequent applications against other enteric bacterial infections in humans that induce significant world wide morbidity and mortality.

Public Health Relevance

Infections of the gastrointestinal tract cause serious diarrheal diseases that are the second leading cause of death due to infection world wide. Few vaccines exist for oral immunization to protect against such pathogens. The technology for generating stable peptide vaccines coupled to a safe effective carrier vehicle would help reduce or eliminate significant morbidity and mortality due to infectious diarrheal diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082655-05
Application #
8485529
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$204,008
Indirect Cost
$57,509
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Salerno-Goncalves, Rosangela; Rezwan, Tasmia; Sztein, Marcelo B (2014) B cells modulate mucosal associated invariant T cell immune responses. Front Immunol 4:511
Fiorentino, Maria; Levine, Myron M; Sztein, Marcelo B et al. (2014) Effect of wild-type Shigella species and attenuated Shigella vaccine candidates on small intestinal barrier function, antigen trafficking, and cytokine release. PLoS One 9:e85211
Waddington, Claire S; Darton, Thomas C; Jones, Claire et al. (2014) An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution. Clin Infect Dis 58:1230-40
Wahid, Rezwanul; Zafar, Shah J; McArthur, Monica A et al. (2014) Live oral Salmonella enterica serovar Typhi vaccines Ty21a and CVD 909 induce opsonophagocytic functional antibodies in humans that cross-react with S. Paratyphi A and S. Paratyphi B. Clin Vaccine Immunol 21:427-34
McArthur, Monica A; Sztein, Marcelo B; Edelman, Robert (2013) Dengue vaccines: recent developments, ongoing challenges and current candidates. Expert Rev Vaccines 12:933-53
Eloe-Fadrosh, Emiley A; McArthur, Monica A; Seekatz, Anna M et al. (2013) Impact of oral typhoid vaccination on the human gut microbiota and correlations with s. Typhi-specific immunological responses. PLoS One 8:e62026
Barry, Eileen M; Pasetti, Marcela F; Sztein, Marcelo B et al. (2013) Progress and pitfalls in Shigella vaccine research. Nat Rev Gastroenterol Hepatol 10:245-55
Eloe-Fadrosh, Emiley A; Rasko, David A (2013) The human microbiome: from symbiosis to pathogenesis. Annu Rev Med 64:145-63
McArthur, Monica A; Sztein, Marcelo B (2013) Unexpected heterogeneity of multifunctional T cells in response to superantigen stimulation in humans. Clin Immunol 146:140-52
Wahid, Rezwanul; Simon, Jakub K; Picking, Wendy L et al. (2013) Shigella antigen-specific B memory cells are associated with decreased disease severity in subjects challenged with wild-type Shigella flexneri 2a. Clin Immunol 148:35-43

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